Effects of Topical Insulin on Second-Degree Burn Wound Healing: Brief Report

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Burns are destructive tissue injuries caused by chemicals, electricity, ultraviolet light, flame, scald, or contact, and are a major public health concern. According to data from 2018, burns account for an estimated 180 000 deaths annually, the majority of cases occurring in low-income countries.¹

Burns can be classified in degrees depending on how deeply and severely they penetrate the skin.² Superficial partial-thickness burns do not involve the deep dermal layers and tend to heal in approximately 21 days. Antibacterial products play an important role in burn wound treatment.² One such example is 1% silver sulfadiazine, a widely used product due to its broad spectrum of action against gram-negative and gram-positive bacteria.^2,3 However, some adverse events associated with 1% silver sulfadiazine have been reported, such as induction of bacterial resistance, poor wound penetration, rapid consumption of silver ions, leukopenia, and renal toxicity.³

Growth factors also promote tissue repair. These substances modulate keratinocyte migration, leading to faster epithelialization. Sadly, they are difficult to manipulate, have a high cost, and are seldom amenable to prolonged storage.⁴

Insulin is a peptide hormone that modulates wound healing.⁵ Studies in animal models and humans have shown that insulin cream accelerates wound healing in hyperglycemic animals,⁵ abbreviates the inflammatory response, induces early neutrophil recruitment, and acts as an anti-inflammatory compound on wounds,⁶ although these effects may be inconsistent.⁷

Insulin cream accelerates the healing of experimental burn wounds in animal models. However, the effects of insulin cream on burn wounds in human patients have not been investigated to date. This brief report was designed to investigate the effects of topical insulin on healing time of second-degree burns.

This was a nonrandomized clinical trial. Participants were recruited from a specialized burn unit. The burn unit is divided into 2 departments, one for hospitalization and one for outpatient care. Written consent was obtained from the patients after they were given information about the procedures to be performed in the study. The patients were selected from the outpatient facility. The study was carried out after approval by the Ethics Committee of the University of Campinas (process number: 2.466.640).

Patients aged over 18 years sustaining second-degree burns in the preceding 72 hours were eligible. Clinical judgment diagnosed the burn depth. Patients with thermal burns affecting up to 20% of total body surface area were included. The total body surface area was estimated according to the literature.⁸ Exclusion criteria were as follows: wounds with signs of infection, need for hospital admission, indications for surgical debridement, history of autoimmune diseases, cutaneous lupus, pyoderma gangrenosum or Stevens-Johnson syndrome, and diabetes. The discontinuation criteria were failure to attend any of the scheduled appointments and withdrawal from the study at any time.

Participants were allocated to 1 of 2 groups: the intervention group (IG), treated with a topical insulin cream formulation, or the control group (CG), treated with 1% silver sulfadiazine. The insulin cream used was prepared with regular insulin (0.5 U/g cream) at the pharmacy of the University of Campinas (Brazil) Hospital under patent number PI 0705370-3.⁵ Wounds were treated according to the following protocol: daily cleansing with 0.9% saline solution, application of a thin layer of the selected product, and occlusion with a sterile gauze dressing. The dressing was performed once daily at home by a patient or caregiver, who previously received guidance on best-practice wound care. Weekly follow-up outpatient appointments were scheduled for wound assessment for signs of localized infection and photographic documentation until complete wound healing was achieved. During follow-up appointments, participants were instructed to evaluate general adverse effects such as headache, heart palpitation, vertigo (due to hypoglycemia), or perilesional itching. The patients were monitored at baseline and then every week until complete healing or at the end of the 4-week follow-up period.

Photographic documentation was carried out using a digital camera (DSC-HX1 9.1 megapixels; Sony Electronics Inc.). A millimeter ruler labeled with appointment date and patient initials was positioned next to the wound. Images were analyzed by a third party using an open-source software (ImageJ).⁹ The outline of the nonepithelized area was drawn using the software drawing tool and a value (mm²) obtained. Wounds with area equivalent to 0 mm² were defined as healed wounds.

Statistical analysis was carried out using SAS v9.4 software. The Mann-Whitney test was used to compare the time (days) required to achieve wound healing between groups. The level of significance was set at 5%. Data distribution was examined using the Shapiro-Wilk test.

The sample comprised 17 participants (8 in the IG and 9 in the CG). The number of burn injuries totaled 12 in the IG and 13 in the CG. Most participants were males (62.5% in IG and 66.7% in CG, respectively) and aged 37.7 ± 18.8 years (IG) or 42 ± 18.8 years (CG). The number of burns caused by exposure to hot liquid (n = 6 in IG and n = 7 in CG, respectively) or flame (n = 2, IG and CG) did not differ significantly between groups (Table). All participants in both groups were seen at the emergency department and received 1% silver sulfadiazine as first-line treatment.

The burns in the CG were located on the right and left lower limbs, left foot, right foot, or right and left forearms. The burns in the IG were located on the right and left upper limbs, right and left forearms, right breast, or right and left hands.    

Healing time was significantly shorter in the IG relative to the CG (9.1 ± 1.9 days and 12.7 ± 3.3 days, respectively, P < .05) as shown in Figure 1. Photographs of second-degree burn wounds of IG and CG patients can be seen in Figure 2. The estimated burn area was similar in both groups (CG 1.44 ± 1.0% and IG 1.42 ± 0.53%).

No hypoglycemic episodes or adverse events were reported over the course of the follow-up period. No signs of wound infection were detected.

Burn wounds requiring medical care are prevalent in Western societies.¹ The healing time of second-degree burns reported in the literature ranges from 14 days for superficial burns to 21 days for deeper burns.² The search for therapies aimed at accelerating lesion epithelialization is justified by the need to reduce the risk of infection, improve scar quality, and lower treatment costs.¹⁰ In the present study, topical insulin application led to a significant decrease in healing time, suggesting a promising effect of this preparation on burn wounds. Patients in the IG and CG had similar sociodemographic characteristics (ie, primarily adult males over 30 years of age) and sustained burn injuries caused by accidental exposure to hot liquid or flame (Table).

Several products can be used to treat burn wounds. However, the level of evidence supporting the ability of such products to improve wound healing is low.¹¹

Successful skin restructuring is dependent on a cascade of ordered events involving cellular and molecular responses and interactions.² Therefore, wound dressings that modulate the healing process may be beneficial relative to conventional products.⁵ Topical insulin is thought to be a relevant therapeutic agent with significant mitogenic effects and an important role in glucose homeostasis regulation, cell growth, and cell differentiation. In a wound healing study with diabetic animals and human patients, insulin promoted monocyte and macrophage migration, pinocytosis, and phagocytosis, and contributed to cell growth and differentiation.⁵ Insulin also stimulated inflammatory cell infiltration and collagen deposition in second-degree burns in hyperglycemic animals compared to controls.⁵

Lack of adverse events in the present study suggests topical insulin treatment is safe and can be indicated as an alternative to antimicrobials. Previous data have shown the beneficial effects of insulin, mainly in diabetic animals and humans.^5,7According to those findings, topical insulin can enhance wound closure, speed up wound healing, and improve wound remodeling by modifying inflammation, thus accelerating epithelialization and neovascularization. Systemic effects (hypoglycemia, hypokalemia, and hypoaminoacidemia) and local effects (infection, pain, and allergenicity) were not observed. Although diabetic patients were excluded from the present study, the findings demonstrate that insulin had beneficial effects, improving wound healing time in nondiabetic patients. Use of topical antimicrobial agents in second-degree burns is a classical approach. In most cases, these agents are aimed at maintaining a moist environment rather than preventing infections, which are uncommon in these wounds.¹²

This brief report has limitations, such as small sample size and nonrandomized design. Even though caregivers received some guidance on how to perform best-practice wound care, it is not known how the recommendations for wound care were implemented. Also, scar quality and treatment costs were not evaluated.

In this study, topical insulin reduced the healing time of second-degree burns compared to conventional treatment. The findings suggest lack of adverse effects of topical insulin, such as hypoglycemia and signs of local infection observed during the follow-up period. While topical insulin and second-degree burns indicated good effects on wound healing without adverse effects, further studies—including clinical studies—would be appropriate to fully establish whether topical insulin can control the bacterial burden.

Acknowledgments: The authors are grateful for the support of this investigation by FAPESP.

Authors: Vagner Franco da Silveira Jr., MD¹; Juliany Lino Gomes Silva, PhD, RN²; Maria Helena Melo Lima, PhD, RN²; and Mario Jose Abdalla Saad, PhD, MD³

Affiliations: ¹Department of Internal Medicine University of Campinas, Tessália Vieira de Camargo, 126 - Cidade Universitária, - Campinas, SP, 13083-887, Brazil; ²School of Nursing, University of Campinas. Tessália Vieira de Camargo, 126 - Cidade Universitária Zeferino Vaz, Campinas, SP, 13083-887, Brazil; ³Department of Internal Medicine University of Campinas, Albert Sabin, s/n - Cidade Universitária, Campinas, SP, 13083-894, Brazil

Funding: The authors acknowledge the support from the São Paulo Research Foundation (FAPESP, process #2014/50907-5).

Disclosure: The authors disclose no financial or other conflicts of interest.

Correspondence: Juliany Lino Gomes Silva, PhD, RN, Tessália Vieira de Camargo, 126. Cidade Universitária Zeferino Vaz. 13083-887 – Campinas, SP, Brazil; julianyl@unicamp.br

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